Partially funded by the Stuart Scott Memorial Cancer Research Fund and the V Wine Celebration in honor of First Responders
Nick Valvano Translational Research Grant*
Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) originate from abnormal blood stem cells which have acquired multiple molecular aberrations over time and generate the bulk tumor cells that are diagnosed in patients in the clinic. Conventional therapies inhibit the bulk tumor cells; however, they do not eliminate the early blood stem cells that are the true root of the disease. Recent work has uncovered unexpected diversity of stem cells in patients with MDS, detected through a new methodology which we recently developed. Cancer/leukemia development is, at least in part, promoted by exposure to environmental toxins. The terrorist attacks on the World Trade Center created an unprecedented environmental exposure to aerosolized dust and gases that contained many carcinogens, and over the past few years we have built a large repository of samples from 9/11 first responder fire fighters, and non-exposed fire fighters as a control. We will leverage this unique sample repository and our newly developed methodology to study over time blood stem cells of individuals who have donate samples to this repository. Our study will be instrumental to improve diagnostic assessment, including at blood the stem cell level, and this may help to improve treatment selection focused on the true root of the disease. In addition, our study may be helpful for the development of treatment strategies for the prevention of leukemia in the future.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Leukemias represent cancers of the blood and are caused by genetic changes (mutations) in our blood cell that drive uncontrolled cell growth. Cancer survivors are more likely to develop leukemia than the general population. Traditionally this was thought to be a consequence of toxicity from the treatments used to fight their cancer, which leads to the development of therapy-related myeloid neoplasm (tMN) one of the most deadly and challenging to treat cancers. However recent studies show that leukemia associated mutations can be found many years before cancer diagnosis and interestingly, these blood mutations can also be seen in healthy people who never develop leukemia. This is phenomenon is called clonal hematopoiesis (CH). Our group has shown that CH is frequent in cancer patients and we find that cancer treatment may promote growth of cells carrying such mutations. To understand the effects of cancer treatment in patients that carry such mutations and how this dictates subsequent progression to leukemia, we propose to study a total of 45,000 cancer patients at time of cancer diagnosis. This will identify individuals with CH at time of diagnosis. We will then follow up patients and study the effects of oncologic therapy to analyzed for the presence of CH and study the effects of distinct cancer treatments on CH. Our study will help us understand tMN and guide the development of interventions to prevent tMN.
Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Gina Gallo
One of the deadliest cancers is called Triple Negative Breast Cancer (TNBC). Women with TNBC are more likely to die of breast cancer than women with other types of breast cancer. This type of cancer is more common in African American women.
Treatments for TNBC exist, but we do not know if they are equally effective for all women with TNBC. One reason the outcome might be poorer for African American women is because the standard treatments might be less effective for them. Treatments for TNBC work better when a woman has a certain mutation in gene called BRCA1 and related genes known as RAD51 genes. Unfortunately, this treatment may not work if the gene has been turned off by a mechanism called methylation. This process of methylation is much more common in African American women. In this proposal, we want to find out how frequent methylation of BRCA1 and RAD51 genes occurs in Caribbean populations and then compare the response to TNBC treatment for African American, Caribbean American and European American populations. We hope to find how frequently BRCA1 gene is turned off in breast cancer patients of Caribbean origins and then use this knowledge to assist in the choice of targeted therapy for these patient populations.
Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Lauren Ackerman
Cancer is considered a disease of the genome because the acquisition of genomic alterations can spur disease progression by disrupting natural checks and balances on cell growth and behavior. These alterations are often a result from exposure to environmental factors, such as UV light or tobacco carcinogens. They also arise as a byproduct of normal physiological processes. One of the most common alterations detected in cancer genomes are mutations that have been linked with our endogenous APOBEC enzymes. The APOBECs normally protect against viral infection by inducing mutations in viral genomes. It is not clear why this potent mutagenic activity turns against our own genomes in the context of cancer. We seek to understand how the anti-viral APOBECs become activated to attack our own genomes and to determine how this activation leads to mutation and cancer growth. We will draw on conceptual parallels between viral infection and cancer-intrinsic processes to gain insights into the mechanisms that drive APOBEC activity in the cancer setting. Our work will set the stage for the development of therapeutic interventions to blunt or leverage this mysterious mutational process.
The last 30 years of research have identified more than 500 genes that are mutated (i.e. defective) in human cancer and a lot of attention has been devoted to these mutations. A central mystery that has not yet been solved is why and how the vast majority of cancers show aneuploidy, i.e. the gain or loss of specific chromosomes (chromosome-specific aneuploidy). For example, tumor cells from colon cancer very often (more than 55% of cases) show in their DNA one extra copy of chromosome 13 (normal cells have 2 copies of chromosome 13, cancer cells have 3/4 copies). If scientists are able to understand what are the consequences of chromosome-specific aneuploidy for cancer cells compared to normal cells, then we will be able use this insight to develop new, more effective treatments, i.e. therapies that specifically target cancer cells while sparing normal cells. The goal of this proposal is to unravel this mystery and begin to use this information to design new therapeutic strategies. To accomplish this task, I will be taking a novel approach. First, we will use normal human cells and we will engineer them to contain an extra copy of a specific chromosome. Then we will utilize a series of experiments to comprehensively characterize the biology of the cells containing the chromosome-specific aneuploidy compared to normal cells. We aim to identify molecules that can specifically kill the aneuploid cells compared to the normal cells, in other words we will look for the “Achilles’ heel” of cancer cells.
Historically, antioxidant supplementation has been viewed as an effective prevention strategy against cancer. Despite this, there is growing evidence that antioxidants support cancer growth and lead to worse patient survival. These findings have changed the way we view antioxidants and the treatment of cancer. This is particularly true in a subset of cancers that are driven by an oncogene called KRAS, which can directly engage an antioxidant program to promote survival in cancer cells. The KRAS oncogene is frequently activated by mutations in pancreatic, colon and lung cancers. However, it has proven extremely difficult to find new drugs that directly inhibit activated KRAS. Currently, patients diagnosed with these cancers are given chemotherapy which also have many side effects due to their general toxicity. Thus, the creation of new therapies which specifically target cancer cells, while sparing other normal, healthy cells, has the potential to increase patient survival while improving their quality of life during therapy. Our laboratory has found that the production of antioxidants by NRF2 is essential for the growth and survival of KRAS-mutant cancer cells. To understand how antioxidants are made and used by cancer cells, we use organoid models—cells grown in three- dimensions to study the role of NRF2 in KRAS-mutant cancers. These results will lead to the creation of new therapies which selectively target cancer cells while sparing healthy cells of the body, leading to better patient health and survival.
The studies of this proposal will address a central question in personalized cancer treatment. Many recent studies have generated three-dimensional tissue models of human tumors, known as organoids, which can be grown and analyzed in the laboratory. Thus, these organoids can be considered “avatars” of their corresponding patient tumors. However, it is unknown whether drugs that affect organoid growth in the laboratory would have similar effects in patients. If so, patient-derived tumor organoids could be used to predict effective treatment.
We will utilize patient avatars to investigate muscle invasive bladder cancer, a highly lethal disease that is treated by chemotherapy followed by surgical removal of the bladder, which drastically affects quality of life. We will use an approach known as “co-clinical trials” to simultaneously test drug response in the clinic with that of patient avatars in the laboratory. In particular, we will determine whether patient avatars are able to predict which patients who have no residual tumor after chemotherapy can safely avoid removal of the bladder.
We have assembled an outstanding research team to investigate whether the response of patient-derived organoids to chemotherapy in the laboratory correlates with the response of the corresponding patients in the clinical trial. In addition, we will examine whether there are specific genetic alterations that are associated with sensitivity to chemotherapy. Consequently, our findings have the potential to greatly improve the standard of care for patients with muscle invasive bladder cancer.
Standard treatment for advanced bladder cancer is platinum-based chemotherapy. Unfortunately, this kind of treatment fails in most patients, and in some, it causes life-threatening heart problems. Today, doctors have no way to figure out who would benefit from platinum-based chemotherapy. Our team of researchers from Memorial Sloan Kettering Cancer Center (MSK) thinks that there are genetic reasons why this kind of chemotherapy works for some patients and not others. Pharmacogenetics is the study of how someone’s genetic make-up influences the way they respond to a drug. The goal of our research is to conduct the most comprehensive pharmacogenetic study to date to identify genetic reasons why some patients respond to chemotherapy and some experience lethal heart problems. The generous funding from the V Foundation will allow us to study the DNA of 500 advanced bladder cancer patients from MSKCC who received platinum-based chemotherapy and were then monitored for treatment response and heart problems. We will use a new genetic tool called the OncoArray to measure over 500,000 common genetic differences in those who respond to chemotherapy and those who do not. In addition, we will perform genetic sequencing to investigate rare genetic differences that may be important. Our study has the potential to enable doctors to tailor treatment to the individual patient in order to deliver the best bladder cancer care possible.
In addition to breast cancer, women who carry a defective copy of the BRCA2 (Breast Cancer Susceptibility) gene live with an incredibly high risk for ovarian cancer. Alterations in the BRCA2 gene can be passed down from parent to child (hereditary mutation) or may arise spontaneously (somatic mutation) in ovarian tumors. The biological role of BRCA2 is to repair damage to the human genome. However, the specific details of how defects in BRCA2 lead to ovarian cancer remain to be defined. The foundation of our collaborative research effort is to elucidate the molecular and genetic wiring that underlie this lethal malignancy. By identifying key players and pathways that drive ovarian tumor growth and treatment resistance, we can expose vulnerabilities that will guide the development of targeted therapies, novel biomarkers, and improve outcomes for patients. One of the highlights of the past two decades of research into BRCA biology was the discovery that patients can be treated with PARP inhibitors, drugs that target a specific DNA repair pathway, resulting in dramatic killing of BRCA deficient tumors. Unfortunately, not all patients respond to PARP inhibitor therapy, and some patients eventually relapse, thus detailed knowledge of the molecular mechanisms that lead to tumor formation and treatment resistance are needed. Our goal in this team-based research effort is to understand how PARP inhibitors selectively target BRCA2 deficient ovarian tumors, identify the molecular routes to PARP inhibitor resistance, and leverage these findings to impact clinical decision rules.
Tumors that spread to the brain, called brain metastases, are the cause of death of half of patients with metastatic melanoma. The metabolic environment of the brain is uniquely low in two amino acids, serine and glycine, which carry messages between nerve cells. This ensures accurate nerve cell communication, but should prevent or slow the growth of tumors, as tumor cells need large amounts of serine and glycine to make DNA and proteins to divide and grow. Yet, tumors can spread to the brain, and are incurable once they have done so.
We hypothesize that tumors metabolically adapt to the brain’s metabolic environment by increasing their ability to make serine and its product glycine, and that blocking the production of serine should either attenuate the development of brain metastases or help treat existing brain metastases. We will determine if serine synthesis is increased in brain metastases, and if tumor cells adapt to, or are selected for, the environment of the brain by increasing their production of serine and glycine. In addition, we have developed small molecules that inhibit serine synthesis, and will test these compounds in mouse models of melanoma brain metastases with the goal of reducing their initiation or growth. These studies will demonstrate that targeting the serine synthesis pathway might be useful in treating melanoma brain metastases and offer proof of concept that small molecule inhibitors of serine synthesis might be effective in treating patients with melanoma brain metastases and brain metastases from other tumors.
